Epilepsy is one of the most prevalent neurological diseases in the world and temporal lobe epilepsy (TLE) is likely the most common form of epilepsy. The treatment strategies for TLE are not satisfactory and as many as 60% of patients with TLE become resistant to currently available antiepileptic drugs. Although the condition can be effectively treated by surgical resection, social and psychological disabilities of the disorder often manifest themselves long before referral to surgery. The mechanisms underlying TLE still remain unclear, although accumulating evidence points to metabolic dysfunction especially in the hippocampus. By elucidating these metabolic alterations, we may reveal new targets for antiepileptic treatment and improve diagnostic criteria. In Papers 2 and 3, we investigated brain metabolism in two mouse models of TLE, namely the pentylenetetrazole (PTZ) kindling model and the pilocarpine status epilepticus model, respectively. Moreover, the antiepileptic efficacy of acetyl-l-carnitine (ALCAR) on seizures and metabolism was evaluated in the PTZ kindling model.

ALCAR is a dietary supplement readily available in health food stores abroad but not in Norway. It is an endogenous compound involved in the transport of acetylmoieties across the mitochondrial membrane. For more than two decades, ALCAR has been evaluated as a therapeutic supplement in various brain disorders, and has shown beneficial effects in small trials with patients with depressive disorders. In rats, single administration of ALCAR increases brain energy availability and protects against various neurotoxic insults such as ischemia and oxidative stress. However, there has been a lack of studies on the effect of chronic ALCAR administration on brain metabolism. In Paper 1, we investigated brain glucose, energy and neurotransmitter homeostasis in mice supplemented with ALCAR for 25 days.

In all three studies constituting this thesis, we obtained detailed maps of the metabolic content in the cerebral cortex and hippocampal formation (HF) of mice using 1H nuclear magnetic resonance (NMR) spectroscopy and high-pressure liquid chromatography. To determine glucose metabolism, we injected mice with 13C labeled glucose and evaluated brain extracts using 1H and 13C NMR spectroscopy and gas chromatography–mass spectrometry.

In Paper 1, we found that ALCAR supplementation increased the amounts of high-energy phosphates in the cortex of mice, indicating increased energy availability. In both brain regions, ALCAR decreased glucose consumption evidenced by increased amounts of glucose and decreased amounts of [3-13C]lactate. Furthermore, ALCAR increased the concentrations of monoamines noradrenaline in the HF and serotonin in cortex. These findings are particularly interesting in relation to a potential antidepressive effect of ALCAR. In Papers 2 and 3, we demonstrated metabolic alterations in epileptic mice, such as glutamate reduction and mitochondrial dysfunction in the HF, partly resembling findings reported in human TLE. Moreover, we revealed that the turnover of important metabolites within and derived from tricarboxylic acid (TCA) cycle intermediates was decreased in both brain regions,consistent with impaired function of the TCA cycle. ALCAR did not affect seizure development in PTZ kindled mice, but attenuated some metabolic alterations.

Altogether, the studies provide new information about metabolic alterations in the brain of epileptic mice and mice treated with ALCAR for 25 days. The findings may help improving diagnostics and treatment of TLE and evaluate the possible role of ALCAR in treating brain disorders.